PROJECT SUMMARY/ABSTRACT The long-term goal of this proposal is to train the applicant to become an independent, academic physician- scientist studying natural and therapeutic immune responses against lung cancer. The principal investigator (PI) has previously obtained Ph.D training in immunology, as well as clinical training in internal medicine and hematology/oncology. He is ABIM board-certified in medical oncology. This application describes a 5-year career development program that will provide the PI a mentored educational experience with the aim of developing new scientific expertise in molecular profiling, high-dimensional analysis, computational biology, and mouse models of human lung adenocarcinoma. At the conclusion of the award period, the PI will have acquired the skills necessary to achieve his ultimate goal of becoming an independent investigator in a academic medical center studying lung cancer immunobiology and immunotherapy, and caring for patients with thoracic malignancies. This research project will capitalize on the expertise and environment of Washington University, which has a long-track record of developing and supporting physician-scientists. Dr. Robert D. Schreiber will mentor the PI's scientific and career development. Dr. Schreiber's work is responsible for the ?immunoediting hypothesis? as well as the demonstration that an immunogenomics approach is able to identify cancer neoantigens, altered proteins resulting from the genomic instability characteristic of malignancy, and use them as a basis for effective personalized cancer vaccines. An advisory committee of scientists will provide additional scientific and career guidance. Lung cancer is the most common cause of cancer-related mortality worldwide. Novel immunotherapy approaches are beneficial for a subset of patients with metastatic lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, but responses are often not durable. The tissue microenvironment of LUAD is characterized by lineages of tumor-associated macrophages (TAM), which suppress T-cell responses. Our laboratory has demonstrated that TAM display a spectrum of activation states ranging from a predominantly anti-inflammatory phenotype in progressively growing tumors to a predominantly pro-inflammatory phenotype in tumors that respond to immunotherapy treatment. In this proposal, we will test the hypothesis that both T-cell dependent and tumor cell-intrinsic signals are required for TAM recruitment into the LUAD microenvironment, and that cancer neoantigens presented by TAM determine the intratumoral function of T-cells mobilized by cancer immunotherapies. For these studies, we will utilize a genetically engineered mouse model of human LUAD that expresses cancer neoantigens previously identified and characterized by our laboratory. This allows us to assess immune responses against both early stage and metastatic cancers. The identification of the precise populations of TAM that constrain anti-tumoral immune responses will have clinically relevant implications with respect to the development of novel immunotherapies for patients with non-small cell lung cancer.